Cardiac output controller

ABSTRACT

This invention is an apparatus for modifying cardiac output of the heart of a subject, including one or more sensors which sense signals responsive to cardiac activity, and a stimulation probe including one or more stimulation electrodes which apply non-excitatory stimulation pulses to a cardiac muscle segment. Signal generation circuitry is coupled to the one or more sensors and the stimulation probe, which circuitry receives the signals from the one or more sensors and generates the non-excitatory stimulation pulses responsive to the signals.

This application claims benefit of provisional application Ser. No.60/026,392 filed Sep. 16, 1996.

FIELD OF THE INVENTION

The present invention relates generally to cardiac therapeutic devices,and specifically to invasive devices for enhancing performance of theheart.

BACKGROUND OF THE INVENTION

Cardiac insufficiency, characterized inter alia by a reduction in thecardiac output, is a common, well-known and well-documented heartmalfunction. It develops as a result of congenital defects or as anend-effect of many diseases. Cardiac output, i.e., the output of theheart per unit time, is the product of stroke volume and heart rate.Hence, variations in cardiac output can be produced by chances incardiac rate or stroke volume. The stroke volume can be influenced, forexample, by changing the strength of cardiac contraction, by changingthe length of the cardiac muscle fibers, and by changing contractilityof cardiac muscle independent of fiber length. The heart rate and rhythminfluence the cardiac output both directly and indirectly, since changesin the rate and rhythm also affect myocardial contractility.

The human body normally regulates the cardiac output in response to bodyneeds by changing the heart rate, as during physical exercise, and/or byadapting the stroke volume. Under pathological conditions, however, someof the normal regulatory mechanisms may be damaged. For example, hearttissue damaged due to myocardial infarct typically cannot sustain normalpumping function, leading to a reduction in stroke volume, and hence ofcardiac output. The body may react to such a reduction by increasing theheart rate, thus imposing long term strain on the heart muscles, leadingin more severe cases to heart failure. There is thus a need for devicesand treatments that can regulate the cardiac output, so as to compensatefor the deficiencies in the normal regulation mechanisms.

In response to this need, modern cardiology has developed means tocontrol various parameters associated with the heart's operation.Pharmaceuticals, for example, may be used to influence the conductionvelocity, excitability, contractility and duration of the refractoryperiod of the heart tissue. These pharmaceuticals are used to treatarrhythmia, enhance cardiac output and prevent fibrillation.Pharmaceuticals are generally limited in effectiveness in that theyaffect both healthy and diseased segments of the heart, usually, with arelatively low precision. They frequently also have unwantedside-effects.

A special kind of control can be achieved using implantable electronicdevices, which provide excitatory electrical stimulation to the heart tocontrol directly the heart rate and/or rhythm. For example, a pacemaker,an electronic devices which is typically implanted in the heart tosupport the heart's electrical excitation system or to bypass a blockedportion of the conduction system. Another type of cardiac electronicdevice is a defibrillator, which senses fibrillation in the heart andapplies a high voltage impulse to “reset” the heart. While electronicpacemakers can control the heart rate, however, they are limited intheir capacity to enhance cardiac output, and they are known to reducestroke volume in at least some instances. Defibrillators are useful intreating arrhythmia when it occurs (although they are painful to thepatient and traumatic to the heart), but they provide no long-termamelioration of cardiac insufficiency.

Thus, none of the treatments known in the art allow effective, long-termregulation of cardiac output. The electromechanical properties of theheart, as well as methods known in the art for influencing theseproperties, are more fully described in the “Background of theInvention” section of PCT patent application PCT/IL97/00012, which isassigned to the assignee of the present patent application and isincorporated herein by reference.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a device and methodfor regulation of hemodynamic parameters, and particularly forincreasing the cardiac output by enhancing the heart's stroke volume.

In preferred embodiments of the present invention, a cardiac outputcontroller comprises a non-excitatory stimulation probe, including oneor more non-excitatory stimulation electrodes; at least one sensor,preferably a sensing electrode; and electronic control circuitry,coupled to the stimulation probe and sensor. The stimulation electrodesand, preferably, the sensor are implanted in the heart of a subject.Alternatively, a sensing electrode may be placed on a body surface. Thecircuitry receives signals from the sensor, indicative of the heart'sactivity, and responsive thereto, drives the stimulation electrodes toprovide non-excitatory electrical stimulation to the heart.

The term “non-excitatory electrical stimulation,” in the context of thepresent patent application and in the claims, refers to electricalpulses that do not induce new activation potentials to propagate incardiac muscle cells. Rather, such pulses generally affect the responseof the heart muscle to the action potentials, possibly by modulatingcell contractility within selected segments of the cardiac muscle.Specifically, as described in the above-mentioned PCT patent applicationPCT/IL97/00012 and incorporated herein by reference, the inventors havefound that by applying non-excitatory electrical stimulation pulses ofsuitable strength, appropriately timed with respect to the heart'selectrical activation, the contraction of the selected segments can beincreased or decreased, thus increasing or decreasing the stroke volumeof the heart. This finding forms the basis for the present invention.

In preferred embodiments of the present invention, characteristics ofthe non-excitatory stimulation are adjusted so as to modify the heart'smuscular activity, thus affecting the cardiac output, preferably byincreasing the stroke volume, without directly affecting the heart rate.Preferably, the device is used to increase cardiac output substantiallycontinuously for extended periods of time, most preferably to boostcardiac output during those portions of a day for which a patient needsincreased blood supply. Accordingly, the device is preferably not usedat night, to allow the heart muscle to rest.

Alternatively, the device may be used to modify the heart's muscularactivity in other ways. For example, in some conditions, such as HOCM(hypertrophic obstructive cardiomyopathy), the device may be operated toreduce cardiac output, so as to reduce the workload on the heart, orparticularly to reduce cardiac muscle contraction in a hypertrophicregion of the heart. As another example, the device may be used toincrease the heart's contraction efficiency, so that a given level ofcardiac output is maintained at a reduced expenditure of energy. Suchuses of the device are described further in a PCT patent applicationentitled, “Apparatus and Method for Controlling the Contractility ofMuscles,” filed on even date (Ser. No. 09/254994, which is assigned tothe assignee of the present patent application, and whose disclosure isincorporated herein by reference.

In any case, the effect of the device on cardiac output is preferablyregulated by changing the timing of the non-excitatory stimulation pulserelative to the heart's activity, preferably relative to the heart'slocal electrical activity or ECG signals received by the sensingelectrode, and/or by changing other pulse characteristics, such as thevoltage, current, duration, polarity, waveform and frequency of thewaveform. Preferably, the device senses the heart's sinus rhythm andapplies and synchronizes the stimulation pulse relative thereto,preferably with a delay before the onset of the stimulation pulse.Additionally, the circuitry may analyze the signals, for example, todetermine the QT interval, so as to adjust the stimulation pulsesresponsive thereto. Alternatively, when the heart's rhythm is irregular,due to ventricular premature beats (VPB's) or other cardiac arrhythmias,the device preferably identifies and analyzes the irregularity, usingsignal processing methods known in the art, and adjusts or withholds thestimulation pulse accordingly.

In some preferred embodiments of the present invention the controlcircuitry is contained within a console external to the body, and theelectrodes are fed percutaneously into the subject's vascular system,for example, through the femoral artery, and are implanted in the heart.Such embodiments are useful particularly in short-term therapy toregulate and stabilize the subject's hemodynamics following an insult ortrauma, for example, open heart surgery or MI.

In alternative preferred embodiments of the present invention, theelectronic control circuitry is contained within a miniaturized,implantable case, similar to pacemaker cases known in the art.

In some preferred embodiments of the present invention, thenon-excitatory stimulation electrodes have a large surface area incontact with the heart tissue, by comparison with intracardiacelectrodes known in the art, such as pacing, or electrophysiologyelectrodes. Preferably, the stimulation electrodes comprise large-areacarbon electrodes, most preferably vitreous carbon, or alternatively,pyro-carbon. Both types of carbon materials are known for theircompatibility with heart tissue, in-vivo durability and excellentelectrical properties, including high electrical conductivity. Thus,they allow a relatively high electrical current to be delivered to arelatively large segment of the heart tissue, without inducingelectrical excitation.

Alternatively, the non-excitatory stimulation electrodes may compriselarge-area electrodes of other types known in the art, such as platinumor platinum/iridium.

In other preferred embodiments of the present invention, thenon-excitatory stimulation electrodes are inserted into one of the bloodvessels of the heart, preferably into the coronary sinus, oralternatively, into a coronary artery. These preferred embodiments arebased on the inventors' experimental findings that cardiac output ismost enhanced when the stimulation electrodes are placed in the heartadjacent to the blood vessels. In one such preferred embodiment, thenon-excitatory stimulation probe comprises a carbon wire electrode,which is inserted into the coronary sinus and passed therein to aposition adjacent the left ventricle.

In some preferred embodiments of the present invention the stimulationprobe comprises a plurality of stimulation electrodes. Preferably, theprobe comprises a stimulation net, which includes a plurality ofinterconnected, individually- and/or collectively- addressableelectrodes, covering a substantial segment of the heart wall. Asdescribed in the above-mentioned '012 PCT application, the inventorshave found that the extent of change in cardiac output, especially inleft ventricular stroke volume, may be controlled by varying the size ofthe segment of the heart to which a non-excitatory field is applied.Such size variation is most preferably achieved by varying the number ofthe electrodes within the net that are to which the non-excitatorystimulation pulse is applied simultaneously.

In another preferred embodiment of this type, different stimulationpulses are applied to respective ones or groups of the plurality ofstimulation electrodes. Preferably, the different stimulation pulses areapplied to the respective electrodes with a predetermined delay betweenthe different pulses. The delay may be varied so as to achieve a desiredhemodynamic effect, for example, to maximize the increase in strokevolume.

In still other such preferred embodiments, the positions of theplurality of stimulation electrodes and/or characteristics of thestimulation pulses applied thereto are optimized responsive to clinicalcharacteristics of the heart. Preferably, before insertion of theelectrodes, a map of the heart is produced, for example, anelectrophysiological map, as described in U.S. Pat. No. 5,568,809, or aphase-dependent geometrical map, as described in PCT Patent ApplicationPCT/IL97/00011, both of which are incorporated herein by reference.Preferably, the map includes information regarding the viability of theheart tissue, for example, based on local contractility or electricalactivity. The non-excitatory stimulation electrodes are then positionedresponsive to the map.

Alternatively or additionally, at the time of implantation of thenon-excitatory stimulation electrodes, their positions are varied andthe results of the variation on hemodynamics are observed, in order tofind optimal, fixed positions for the electrodes. A similar effect maybe attained by implanting the net electrode, as described above, andvariably addressing different ones or groups of electrodes in the net soas to optimize the hemodynamic effect.

In alternative embodiments of the present invention, the non-excitatorystimulation probe comprises at least one hybrid electrode. The hybridelectrode preferably comprises a sensing core, preferably a platinum orplatinum/iridium electrode, surrounded by an annular non-excitatorystimulation electrode, preferably comprising a carbon electrode, asdescribed above.

In still other embodiments of the present invention, a single electrodemay serve as both the sensing electrode and as one of the one or morestimulation electrodes.

In some preferred embodiments of the present invention at least onenon-excitatory stimulation electrode and the sensing electrode areimplanted in the same chamber of the heart, preferably in the leftventricle. Preferably, the non-excitatory stimulation electrode is fixedagainst the wall of the left ventricle, and the sensing electrode isfixed at the septum thereof. Alternatively, the stimulation and sensingelectrodes may be implanted in different chambers of the heart, ineither the ventricles or the atria. The delay between the heart activitysignal sensed by the sensing electrode and the pulse applied to thestimulation electrode is preferably dependent on the relative postionsof these electrodes.

In some preferred embodiments of the present invention, thenon-excitatory stimulation electrodes comprise a bipolar electrode, andthe non-excitatory stimulation pulse is provided to the heart tissuebetween the poles of the electrode. In other preferred embodiments, thenon-excitatory stimulation pulse is provided between the one or morestimulation electrode and another electrode, for example, the sensingelectrode. Alternatively, the pulse may be applied between thestimulation electrodes and the case of the control circuitry, in thoseembodiments of the present invention in which the case is implanted inthe patient's body, as described above.

In preferred embodiments of the present invention, the control circuitryapplies to the stimulation electrodes a square wave stimulation pulsehaving current up to 50 mA, most preferably between 5 and 10 mA, for aduration that may be nearly as long as the beat-to-beat interval of theheart, most preferably between 30 and 50 msec. Preferably, thestimulation pulse is followed by a pulse of opposite polarity, toprevent problems of electrode degradation and polarization.

In some preferred embodiments of the present invention, an alternatingwaveform is superimposed on the square wave pulse. The waveform isitself preferably a square wave or, alternatively a sinusoidal or asawtooth wave, having a frequency up to 10 kHz and amplitude less thanor comparable to that of the square wave pulse. The inventors have foundthat in at least some cases, such a waveform enhances the hemodynamiceffect of the non-excitatory stimulation pulse on the heart muscle.

In some preferred embodiments of the present invention, the controlcircuitry also receives a sensor signal indicative of hemodynamicconditions, preferably indicative of the cardiac output, and adjusts thestimulation pulse responsive to the signal to achieve a desired cardiacoutput level. Alternatively or additionally, physiological sensors maybe used to sense other hemodynamic parameters, such as blood pressure orblood oxygenation, so as to provide feedback signals to the controlcircuitry or to telemetry apparatus associated with the controlcircuitry. Sensors used for this purpose may thus include flow ratesensors, pressure sensors, temperature sensors, oxygen sensors, andother types of sensors known in the art. The control circuitry thenadjusts the stimulation pulse so that the hemodynamic parameters aremaintained within a desired range of values.

Although preferred embodiments of the present invention are describedfor the most part with reference to sensing electrogram signals in theheart, so the cardiac output controller applies the non-excitatorystimulation pulse in response to and generally synchronized with thesinus rhythm, cardiac output controllers in accordance with the presentinvention may also be synchronized by other methods. For example, asdescribed above, the non-excitatory stimulation pulse may besynchronized relative to a body-surface ECG, and may also besynchronized and controlled relative to an arrhythmic heart beat.

Alternatively, the pulse may be externally synchronized, for example byan externally-applied trigger pulse or by a pacing pulse that is appliedto the heart. These aspects of the present invention are furtherdescribed in a PCT patent application filed on even date, entitled“Cardiac Output Enhanced Pacemaker” Ser. No. 09/254,900, which isassigned to the assignee of the present application, and whosedisclosure is incorporated herein by reference.

Preferred embodiments of the present invention may also be used inconjunction with suitable drugs, as described in a PCT patentapplication entitled “Drug-Device Combination for Controlling theContractility of Muscles” Ser. No. 09/254,993, and in conjunction withdevices and methods for preventing cardiac fibrillation, as described ina PCT patent application entitled “Fencing of Cardiac Muscles” Ser. No.09/254,903, both filed on even date and assigned to the assignee of thepresent application. The disclosures of these applications areincorporated herein by reference.

There is therefore provided, in accordance with a preferred embodimentof the present invention, apparatus for modifying cardiac output of theheart of a subject, including:

one or more sensors, which sense signals responsive to cardiac activity;

a stimulation probe including one or more stimulation -electrodes, whichapply non-excitatory stimulation pulses to a cardiac muscle segment; and

signal generation circuitry, coupled to the one or more sensors and thestimulation probe, which circuitry receives the signals from the one ormore sensors and generates the non-excitatory stimulation pulses,responsive to the signals.

Preferably, the signal generation circuitry is contained in a unitexternal to the subject's body, or alternatively, in an implantablecase.

Preferably, application of the stimulation pulses engenders an increasein the cardiac output, or alternatively, a decrease in the cardiacoutput.

Alternatively or additionally, application of the stimulation pulsesincreases an efficiency of contraction of the heart.

Preferably, the one or more sensors include a intracardiac electrode,and the signal generation circuitry synchronizes the stimulation pulseto electrical activity of the heart. Alternatively, the one or moresensors includes a body surface electrode, and the signal generationcircuitry synchronizes the stimulation pulse to an ECG signal.Preferably, the signal generation circuitry identifies an arrhythmia inthe signals and controls the stimulation pulses responsive thereto.Additionally or alternatively, the signal generation circuitry detects aQT interval in the signals and controls the stimulation pulsesresponsive thereto.

Preferably, the signal generation circuitry varies one or moreparameters of the stimulation pulse, from the group of parametersincluding voltage, current, duration, timing delay, waveform andwaveform frequency. After the non-excitatory stimulation pulse, thesignal generation circuitry generates another pulse of opposite polarityto the stimulation pulse, which is applied to the cardiac muscle segmentby the stimulation probe.

Preferably, the one or more stimulation electrodes apply the stimulationpulse to a heart segment having an area of at least 5 mm², morepreferably at least 1 cm², and most preferably at least 4 cm².

In a preferred embodiment of the invention, the signal generationcircuitry varies the area of the heart segment to which the stimulationpulse is applied. Preferably, the stimulation probe includes a net ofelectrodes, which are addressable such that an extent of the segment towhich the stimulation pulses is applied is controlled by addressingselected electrodes in the net. Preferably, the circuitry appliesmultiple, different stimulation pulses, preferably a time sequence ofpulses, to different ones of the electrodes in the net.

In another preferred embodiment of the invention, the stimulation probeincludes a hybrid electrode, including the intracardiac electrodetogether with at least one of the one or more stimulation electrodes.Preferably, the hybrid electrode includes a core section including thesensing electrode, enclosed within an annular section including the atleast one stimulation electrode, wherein the annular section preferablyincludes a carbon material.

In still another preferred embodiment, the one or more stimulationelectrodes include an elongate electrode, which is inserted into a bloodvessel of the heart.

Preferably, the one or more stimulation electrodes include vitreouscarbon or, alternatively, pyrolitic carbon.

In a preferred embodiment of the invention the one or more sensorsinclude a hemodynamic sensor, which generates signals responsive to ahemodynamic parameter. Preferably, the hemodynamic sensor generates thesignals responsive to blood flow. Alternatively or additionally, thehemodynamic sensor generates the signals responsive to blood oxygenationand/or temperature. Preferably, the one or more sensors include anelectrode, which senses cardiac electrical activity.

Preferably, the apparatus includes a telemetry device, which receivesthe signals from at least one of the one or more sensors and controlsthe signal generation circuitry to adjust the non-excitatory stimulationpulse.

There is further provided, in accordance with a preferred embodiment ofthe present invention, a method for modifying cardiac output,including.:

applying a stimulation probe including one or more stimulationelectrodes to a subject's heart;

receiving a signal from at least one sensor responsive to the subject'scardiac muscle activity;

generating a non-excitatory stimulation pulse responsive to the signaland conveying the pulse to at least one of the one or more electrodes.

Preferably, receiving the signal includes introducing a sensingelectrode into the heart and receiving signals therefrom, and generatingthe stimulation pulse includes generating a pulse synchronized withelectrical activity sensed by the sensing electrode.

Alternatively or additionally, receiving the signal includes applying anelectrode to a body surface and receiving signals therefrom, and whereingenerating the stimulation pulse includes generating a pulsesynchronized with an ECG signal.

Further alternatively or additionally, receiving the signal includesreceiving signals from at least one of the one or more stimulationelectrodes.

Preferably, generating the stimulation pulse includes generating a pulsehaving a predetermined delay relative to the signal.

In a preferred embodiment of the invention, applying the stimulationprobe includes applying a probe including a plurality of stimulationelectrodes, and generating and conveying the pulse includes generating asequence of pulses and applying each pulse in the sequence to adifferent one of the plurality of stimulation electrodes.

Preferably, generating and conveying the stimulation pulse includesgenerating and conveying stimulation pulses selectively, based on acharacteristic of the signals received from the at least one sensor.Further preferably, generating and conveying the pulses includesgenerating and applying pulses at a rate dependent on the heart rate,but not equal to the heart rate. Alternatively or additionally,generating and conveying the pulses includes detecting a cardiacarrhythmia and adjusting the application of the pulses responsivethereto. Further additionally or alternatively, generating and conveyingthe pulses comprises detecting a QT interval in the signals andgenerating pulses responsive thereto.

Preferably, generating the non-excitatory stimulation pulse includesvarying one or more parameters of the pulse, selected from the groupincluding the pulse voltage, current, duration, delay, waveform andwaveform frequency.

Further preferably, the pulse includes a baseline pulse and a waveform,preferably a square wave, of substantially higher frequency than thebaseline pulse superimposed thereon. Preferably, after generating thenon-excitatory stimulation pulse another pulse of opposite polaritythereto is generated and conveyed to the electrodes.

In a preferred embodiment of the invention, applying the non-excitatorystimulation pulse includes varying the extent of a portion of the areaof the heart segment to which the stimulation pulse is applied, whereinvarying the extent preferably includes selectively addressing a net ofstimulation electrodes implanted in the heart.

In another preferred embodiment, applying the stimulation probe includesinserting the one or more stimulation electrodes in multiple chambers ofthe heart.

In still another preferred embodiment, implanting the stimulation probeincludes inserting at least one of the one or more stimulationelectrodes into a blood vessel of the heart, preferably into thecoronary sinus.

In a preferred embodiment of the invention, receiving the signalincludes sensing a hemodynamic parameter, preferably sensing cardiacoutput, wherein generating the pulse preferably includes changing thepulse responsive to the signal to increase the cardiac output, oralternatively, to decrease the cardiac output.

Alternatively or additionally, sensing the hemodynamic parameterincludes sensing a pressure and/or a flow rate and/or oxygenation and/ora temperature.

In another preferred embodiment of the invention, generating andconveying the pulse includes generating and conveying pulses at selectedtimes of day, preferably conveying pulses to increase cardiac outputduring the subject's waking hours.

Preferably, generating and conveying the pulses includes generating andconveying pulses which increase the subject's cardiac output, oralternatively decrease the subject's cardiac output. Furtheralternatively or additionally, generating and conveying the pulsesincludes generating and conveying pulses which increase the efficiencyof contraction of the heart.

Preferably, conveying the pulses includes applying pulses to a heartsegment having an area of at least 5 mm², more preferably at least 1cm², and most preferably at least 4 cm².

The present invention will be more fully understood from the followingdetailed description of the preferred embodiments thereof, takentogether with the drawings in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic illustration showing a device for controllingcardiac output, in accordance with a preferred embodiment of the presentinvention;

FIG. 1B is a schematic illustration showing a miniaturized implantabledevice for controlling cardiac output, in accordance with an alternativepreferred embodiment of the present invention;

FIG. 2A is a schematic sectional illustration showing the heart of apatient, into which stimulation and sensing electrodes for use inconjunction with the device of FIG. 1A are inserted, in accordance witha preferred embodiment of the present invention;

FIG. 2B is a schematic illustration of a non-excitatory stimulationprobe, in accordance with another preferred embodiment of the presentinvention;

FIG. 3 is a schematic block diagram of control circuitry use in thedevices depicted in FIG. 1A, in accordance with a preferred embodimentof the present invention;

FIG. 4 is a flow chart illustrating a method of regulating cardiacoutput, in accordance with a preferred embodiment of the presentinvention;

FIG. 5 is a schematic illustration showing a square wave stimulationpulse applied by stimulation electrodes to the patient's heart, inaccordance with a preferred embodiment of the present invention;

FIG. 6 is a schematic illustration of a stimulation electrode for use inconjunction with the devices of FIGS. 1A and 1B, in accordance with apreferred embodiment of the present invention;

FIG. 7 is a schematic illustration of a hybrid electrode for use inconjunction with the devices of FIGS. 1A and 1B, in accordance with analternative preferred embodiment of the present invention; and

FIGS. 8-32 are electronic schematic electronic diagrams showingcircuitry for use in the device of FIG. 1A, in accordance with apreferred embodiment of the present invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

FIG. 1A schematically illustrates a device 20 for regulating cardiacoutput, comprising a control unit 27, an implantable non-excitatorystimulation probe 21, including at least one non-excitatory stimulationelectrode 23, and an implantable sensing electrode 29. Control unit 27includes signal generation circuitry 22 (shown in FIG. 3 below anddescribed with reference thereto), as well as an optional display 24 anda control panel 26. When properly implanted in the heart, as describedbelow, sensing electrode 29 receives local electrogram signals from theheart muscle and transmits them to the signal generation circuitry 22.The circuitry generates a non-excitatory stimulation pulse responsive tothe electrogram signal, which pulse is applied by probe 21 to cardiacmuscle tissue. Control unit 27 optionally also includes an externaltrigger input 30. Device 20 may further include another physiologicalsensor 31, for example, a flow sensor, for determining the effect of thestimulation provided by the device on the cardiac output.

FIG. 1B schematically illustrates device 20 in accordance with analternative preferred embodiment of the present invention, in whichsignal generation circuitry 22 is contained in an implantableminiaturized electronic control circuitry case 32, similar toimplantable pacemaker cases known in the art. Unlike control unit 27,case 32 does not include display 24 and control panel 26, but in otherrespects, the embodiment of FIG. 1B is functionally similar to that ofFIG. 1A.

In the embodiment shown in FIG. 1B, stimulation electrode 23 is shown tobe a relatively large area electrode, designed to provide stimulation anarea of at least 5 mm² in the heart. Electrode 23 preferably comprises alow-resistance carbon material, preferably vitreous carbon, oralternatively, pyrolitic carbon. Electrodes made of such materials aremanufactured, for example, by Sorin Biomedica, of Saluggia, Italy, andby Goodfellow Cambridge Ltd., of London, England. Both types of carbonmaterials are known for their compatibility with heart tissue, in-vivodurability and excellent electrical properties. It will be understood,however, that other types of electrode materials made also be used, suchas various types described in A Guide to Cardiac Pacemakers,Defibrillators and Related Products, by Morse, et al. (Droege ComputingServices, Durham, N.C.), which is incorporated herein by reference.Stimulation probe 21 may comprise more than a single stimulationelectrode. Sensing electrode 29 may comprise any suitable type ofintracardiac electrode, known in the art.

Preferably, electrodes 23 and 29 are coated with an anticoagulant, suchas heparin, preferably in a time-release form, or elute theanticoagulant into the heart tissue, to prevent clot formation on andaround the electrodes. Such electrodes may be produced in a mannersimilar to steroid-eluting electrodes known in the art, for example, theMedtronic CAPSURE model 4003 electrode, described in The Foundations ofCardiac Pacing, by Sutton and Bourgeois, p. 73, which is incorporatedherein by reference.

FIG. 2A is a schematic illustration showing electrodes 23 and 29implanted in a subject's heart 38, in accordance with a preferredembodiment of the present invention. Electrodes 23 and 29 are implantedin a chamber of the heart, preferably both in left ventricle 34. Mostpreferably, non-excitatory stimulation electrode 23 is implanted incontact with the wall of left ventricle 34, and sensing electrode 29 isimplanted in septum 36, between the ventricles. Electrodes 23 and 29 areconnected by wires passing through aorta 39 to either control unit 27outside the body or to implantable case 32, which is preferablyimplanted in the patient's chest. When circuitry 22 detects anelectrical activation pulse in the electrogram signal received fromelectrode 29, it generates a stimulation pulse, which is applied toelectrode 23, preferably so as to increase the contraction of at leastthe segment or the wall of ventricle 34 with which electrode 23 is incontact, thus increasing the ventricular stroke volume.

Alternatively, stimulation electrode 29 and, optionally, sensingelectrode 23 may be implanted surgically, preferably in the epicardium.

FIG. 2B is a schematic illustration showing an alternative preferredembodiment of the present invention, in which non-excitatory stimulationprobe 21 comprises a wire electrode 33. The electrode, which preferablycomprises carbon material, as described above, is connected by aninsulated conductor 43 to circuitry 22. It is preferably implanted inone of the blood vessels of the heart. Most preferably, electrode 33 ispassed through the right atrium of the heart, into the coronary sinus,using techniques of catheterization known in the art, and is positionedtherein adjacent to left ventricle 34. The electrode is then driven bycircuitry 22 to deliver the non-excitatory stimulation pulses to theheart wall, as described herein.

FIG. 3 is a schematic block diagram of signal generation circuitry 22,in accordance with a preferred embodiment of the present invention.Circuitry 22 comprises a stimulation section 100, a detection circuit104 and a sensing, unit 110. Unit 110 receives and conditionselectrogram signals from sensing electrode 29. Detection circuit 104senses a local activation wave in the electrogram, preferably bydetecting a slope and voltage level corresponding to the rising edge ofthe wave, as is known in the art, and generates a trigger pulseresponsive thereto. The trigger pulse is conveyed to stimulation section100, which generates the stimulation pulses and applies these pulses tothe electrodes of stimulation probe 21.

Sensing, unit 110 includes signal blanking unit 101 and signal blanklogic 102 and a differential amplifier and signal conditioning circuit103. The blanking operates to block the input to detection circuit 104while the output of stimulation section 100 is active, to prevent agothe system from generating trigger pulses due to stimulation artifacts.

Stimulation section 100 comprises a trigger divider 105, which generatesa modified trigger pulse in response to input trigger pulses fromdetection circuit 104 or alternatively from external trigger input 30.The trigger divider allows a user of device 20 to select whether thestimulation pulse will be applied at every heart beat or only once in apredetermined number of beats. Section 100 further includes signalgenerators 106 and 107, which generate voltage signals of predefinedcharacteristics, as described below, in response to the modified triggerpulse, and constant current units (CCU) 108 and 109, which convert inputvoltage signals from the signal generators to output current pulses. Twostimulation output channels are shown in FIG. 3, enabling differentstimulation pulses to be applied to two or more different stimulationelectrodes. It will be appreciated, however, that only one of thechannels need be used or alternatively, that additional channels may beadded to drive additional stimulation electrodes.

FIG. 4 is a flow chart, which summarizes a method for regulation ofcardiac output using device 20, according to a preferred embodiment ofthe present invention. Preferably, parameters of the stimulation pulse,such as its level, duration, delay and waveform characteristics, asdescribed below, are preset by the user. Sensing electrode 29 senseselectrogram signals, as described above, and signal generation circuitry22 receives these signals and inputs them to detection circuit 104,which detects heart activity, preferably the sinus rhythm, and generatesa trigger pulse responsive thereto. The trigger pulse drives stimulationsection 100 to generate the stimulation pulse, which is applied to theheart by stimulation electrode 23. In an alternative preferredembodiment, an external trigger coupled to input 30 is employed.

Optionally, physiological parameters related to the cardiac output aremonitored in order to verify the efficacy of the non-excitatorystimulation. For example, flow of blood through aorta 39 may be detectedby flow sensor 31, as illustrated in FIG. 2A. Preferably, at least someof the parameters of the stimulation pulse, for example, its amplitudeand/or timing, are adjusted responsive to the monitored parameters so asto achieve a desired cardiac output level. Such monitoring andadjustment are preferably carried out on-line, for example, by controlunit 27 itself. Alternatively or additionally, a separate telemetry unit(not shown in the figures) monitors the parameters and is used toprogram control unit 27 to vary the parameters of the stimulation pulseaccordingly.

FIG. 5 is a schematic illustration of a non-excitatory stimulation pulse51 applied by stimulation electrode 23 to cardiac tissue, in accordancewith a preferred embodiment of the present invention. In some preferredembodiments of the present invention the regulation of cardiac output isachieved by varying certain characteristics of pulse 51. Non-excitatorystimulation energy is applied to stimulation electrode 23 in the form ofa baseline pulse 53 having a baseline amplitude, indicated by an arrow54 in FIG. 5, of preferably 5 to 10 mA, optionally up to 50 mA. Theduration of pulse 51, indicated by an arrow 52, preferably rangesbetween 30 and 80 ms, and optionally up to 500 ms. Pulse 53 ispreferably followed by another pulse of opposite polarity (not shown inthe figure) to prevent problems of tissue polarization and electrodedegradation, as described in the above-referenced '012 PCT applicationand mentioned above. Preferably, a waveform 58 having a frequency of upto 10 kHz and amplitude, indicated by an arrow 56, up to or comparableto the baseline amplitude is superimposed on the baseline amplitude ofpulse 53. Although waveform 58 is shown here as a square wave, any othersuitable waveform may be used, for example, a sinusoid or sawtooth wave.

Preferably, waveform 51 is triggered upon the detection of the risingedge of the R-wave of the heart's electrical activity by detectioncircuit 104. Alternatively, signal generators 106 and 107 may becontrolled to provide a delay, indicated by an arrow 50 in FIG. 5, ofbetween 1 and 500 msec between the trigger input and the pulsegeneration. The appropriate delay may depend on whether the trigger isprovided by detection circuit 104 or by external trigger 30, as well ason the relative positions of sensing electrode 29 and sensing electrode23. The delay is adjusted based on the desired increase or decrease ofcardiac output that is to be achieved, and the optimal delay willgenerally vary from patient to patient.

FIG. 6 is a schematic illustration showing an electrode net 40, for useas part of stimulation probe 21, in accordance with a preferredembodiment of the present invention. Net 40 comprises a plurality ofstimulation electrodes 35, preferably, interconnected by a conductornetwork 37. Electrodes 35 are preferably individually and/orcollectively addressable, and may operate in either a unipolar or abipolar mode. Net 40 is preferably large enough to cover a substantialsegment of the heart wall, preferably at least 1 cm² and most preferablyat least 4 cm². Each individual electrode 35 preferably has an area ofat least 5 mm², and is separated from its neighbors preferably by atleast 1 cm.

In this preferred embodiment, cardiac output regulation is preferablyachieved through variation of the stimulated area of a segment of theheart wall with which net 40 is in contact, as described in the '012 PCTpatent application. Preferably, the stimulated area is varied bychanging the active area of net 40, i.e., varying the extent of the areaof the net over which electrodes 35 are driven to deliver electricstimulation to the heart. The inventors have found, for example, thatwhen the non-excitatory stimulation is applied between pairs ofelectrodes, selected among a plurality of electrodes placed in the leftventricle, the resultant enhancement of left-ventricular pressure andcardiac output varies responsive to the relative positions of theelectrodes in the pair and the distance between them. Electrodes 35 innet 40 may thus be selectably addressed to optimize the hemodynamicresults of the stimulation. Moreover, electrodes 50 may also be used assensing electrodes, to map cardiac electrical activity over the segmentof the heart wall, so that the stimulation may be applied responsive tothe map.

FIG. 7 schematically illustrates a hybrid electrode probe 41 for usewith device 20, in accordance with an alternative preferred embodimentof the present invention. Probe 41 comprises an annular stimulationelectrode 32, preferably a carbon electrode, as described above,surrounding a smaller sensing electrode 42 at the center of the probe,preferably, a platinum or platinum/iridium electrode, most preferablybipolar. It will be understood that the methods, stimulation waveformsand control electronics described above in relation to electrode 23 maybe applied using probe 41, as well as any other suitable electrodeconfiguration. Probe 41 is advantageous in that it reduces the number ofseparate electrodes that need to be introduced into and implanted in theheart.

FIGS. 8-31 are electronic schematic diagrams illustrating circuitry foruse in implementing the functions of circuitry 22, in accordance with apreferred embodiment of the present invention. As shown in FIGS. 8A and8B, the circuitry includes an ECG processor 130, a first CCU section140, and main control circuit 150, which together perform the functionsof circuitry 22, as shown in FIG. 3 and described with referencethereto. In addition, a second CCU section 142 is designed to provide,optionally, excitatory stimulation pulses, i.e., to pace the heart. Thiselement is beyond the scope of the present invention, however, and isdescribed in detail in the above-mentioned PCT patent applicationentitled “Cardiac Output Enhanced Pacemaker,” filed on even date andincorporated herein by reference.

FIGS. 9 through 31 are circuit diagrams showing details of theimplementation of the elements of FIGS. 8A and 8B. These diagrams areconsidered sufficient in and of themselves to enable one skilled in theart to practice the present invention. Various aspects of these diagramsare described hereinbelow.

FIGS. 9A, 9B and 9C illustrate main control circuit 150, which is basedon a microcontroller MPU 1, preferably an 8051-type microcontroller, asis known in the art. The microcontroller receives user commands via acommunications interface, for example, to program parameters of thestimulation pulses to be applied. It controls other elements ofcircuitry 22 via a data bus, marked AD0-AD7.

FIGS. 10A and 10B show details of ECG processor 130, which receiveselectrical signals from the patient's body and processes them togenerate trigger pulses, as described above, for driving thenon-excitatory stimulation. ECG processor 130 includes an ECG amplifier152, an ECG signal conditioning unit 154, an A/D converter 156, and adetection controller 158. ECG amplifier 152 is shown in detail in FIG.11, and comprises a differential preamplifier and programmable gainamplifier and blanking unit. Signal conditioning unit 154, shown inFIGS. 12A and 12B, includes programmable high-pass, low-pass and notchfilters, selectable by means of a clock generator, and also including ananalog switch for bypassing the notch filter. A/D converter 156 is shownin FIG. 13. FIGS. 14A and 14B illustrate controller 158, includinganother 8051-type microcontroller MPU2, which analyzes the ECG signaland generates the trigger pulse.

FIGS. 15A, 15B and 15C illustrate first CCU section 140, which generatestwo channels of non-excitatory stimulation pulses. CCU section 140includes two control units 162 and 164, waveform generators 166 and 168,power units 170 and 174, and a waveform selector 172. FIGS. 16A and 16Bshow details of waveform generator 166, which drives a first one of thetwo non-excitatory channels, while FIGS. 19A and 19B show waveformgenerator 168, which is substantially similar to generator 166 anddrives the second channel. FIGS. 17A, 17B and 17C illustrate controlunit 162, which receives and scales the waveform from generator 166.FIG. 17C shows timing control logic common to both control units 162 and164. FIGS. 20A, 20B, 20C and 20D illustrate control unit 164, whereinFIGS. 20A and 20B show waveform scaling circuitry similar to that inFIGS. 17A and 17B. FIGS. 20C and 20D include circuitry for controllingthe relative delays of the pulses generated by the two stimulationchannels. FIGS. 18 and 21 show details of power units 174 and 178,respectively, and FIG. 22 illustrates wave selector 176.

FIG. 23 shows second CCU section 142, including two CCU channels 180 and182, for generating pacing pulses at predetermined rates and a relativedelay therebetween, similar to pacemakers known in the art. FIGS. 24A,24B and 24C show details of channel 180. FIGS. 25A and 25B show detailsof channel 182, which is switched by the same switch and counters aschannel 180 (shown in FIG. 24B).

FIGS. 26, 27A, 27B, 28, 29A and 29B show details of isolation circuitry,which is used when circuitry 22 is to be run while connected to externalpower. FIG. 30 illustrates a battery charging circuit. FIGS. 31 and 32show front and rear panel connections, respectively.

Although in some of the preferred embodiments described above, as shownin FIG. 1B, for example, circuitry 22 is shown as being contained withinan implantable case 32, the specific implementation of the circuitryexemplified by FIGS. 8-32 is better stilted to be contained in anexternal, bedside case, for example, control unit 27, shown in FIG. 1A,in accordance with the best mode of the invention as it is practiced atpresent. It will be understood that the circuitry of FIGS. 8-32 can besuitably altered and miniaturized to fit in an implantable case, usingmethods and electronic devices known in the art, particularly such asare currently used in implantable pacemakers. On the other hand, undersome circumstances, non-excitatory stimulation and cardiac outputregulation may be best accomplished using such an external, bedsidecase, when the cardiac output must be regulated temporarily, forexample, during recovery from infarction or surgery.

It will be appreciated that the preferred embodiments described aboveare cited by way of example, and the full scope of the invention islimited only by the claims.

What is claimed is:
 1. Apparatus for modifying cardiac output of theheart of a subject, comprising: one or more sensors, which sense signalsresponsive to cardiac activity; a stimulation probe comprising one ormore stimulation electrodes, which apply non-excitatory stimulationpulses to a cardiac muscle segment; and signal generation circuitry,coupled to the one or more sensors and the stimulation probe, whichcircuitry receives the signals from the one or more sensors andgenerates non-excitatory stimulation pulses, only at a time at whichthey are unable to propagate action potentials responsive to thesignals, wherein the signal generation circuitry identifies anarrhythmia in the signals and controls the stimulation pulses responsivethereto.
 2. Apparatus for modifying cardiac output of the heart of asubject, comprising: one or more sensors, which sense signals responsiveto cardiac activity; a stimulation probe comprising one or morestimulation electrodes, which apply non-excitatory stimulation pulses toa cardiac muscle segment; and signal generation circuitry, coupled tothe one or more sensors and the stimulation probe, which circuitryreceives the signals from the one or more sensors and generates thenon-excitatory stimulation pulses, responsive to the signals, whereinthe signal generation circuitry detects a QT interval in the signals andcontrols the stimulation pulses responsive thereto.
 3. Apparatus formodifying cardiac output of the heart of a subject, comprising: one ormore sensors, which sense signals responsive to cardiac activity; astimulation probe comprising one or more stimulation electrodes, whichapply non-excitatory stimulation pulses to a cardiac muscle segment; andsignal generation circuitry, coupled to the one or more sensors and thestimulation probe, which circuitry receives the signals from the one ormore sensors and generates the non-excitatory stimulation pulses,responsive to the signals, wherein the one or more stimulationelectrodes apply the stimulation pulse to a heart segment having an areaof at least 1 cm².
 4. Apparatus according to claim 3, wherein the one ormore stimulation electrodes apply the stimulation pulse to a heartsegment having an area of at least 4 cm².
 5. Apparatus for modifyingcardiac output of the heart of a subject, comprising: one or moresensors, which sense signals responsive to cardiac activity; astimulation probe comprising one or more stimulation electrodes, whichapply non-excitatory stimulation pulses to a cardiac muscle segment; andsignal generation circuitry, coupled to the one or more sensors and thestimulation probe, which circuitry receives the signals from the one ormore sensors and generates the non-excitatory stimulation pulses,responsive to the signals, wherein the one or more stimulationelectrodes apply the stimulation pulse to a heart segment having an areaof at least 5 mm², and wherein the signal generation circuitry variesthe area of the heart segment to which the stimulation pulse is applied.6. Apparatus for modifying cardiac output of the heart of a subject,comprising: one or more sensors, which sense signals responsive tocardiac activity; a stimulation probe comprising one or more stimulationelectrodes, which apply non-excitatory stimulation pulses to a cardiacmuscle segment; and signal generation circuitry, coupled to the one ormore sensors and the stimulation probe, which circuitry receives thesignals from the one or more sensors and generates non-excitatorystimulation pulses, only at a time at which they are unable to propagateaction potentials responsive to the signals, wherein the stimulationprobes comprises a net of electrodes.
 7. Apparatus according to claim 6,wherein the electrodes in the net are addressable, such that an extentof the segment to which the stimulation pulses is applied is controlledby addressing selected electrodes in the net.
 8. Apparatus according toclaim 6, wherein the circuitry applies multiple, different stimulationpulses to different ones of the electrodes in the net.
 9. Apparatusaccording to claim 8, wherein the multiple, different stimulation pulsescomprises a time sequence of pulses.
 10. Apparatus for modifying cardiacoutput of the heart of a subject, comprising: one or more sensors, whichsense signals responsive to cardiac activity; a stimulation probecomprising one or more stimulation electrodes, which applynon-excitatory stimulation pulses to a cardiac muscle segment; andsignal generation circuitry, coupled to the one or more sensors and thestimulation probe, which circuitry receives the signals from the one ormore sensors and generates the non-excitatory stimulation pulses,responsive to the signals, wherein the one or more sensors comprise anintracardiac electrode, and wherein the signal generation circuitrysynchronizes the stimulation pulse to electrical activity of the heart,and wherein the stimulation probe comprises a hybrid electrode,including the intracardiac electrode together with at least one of theone or more stimulation electrodes.
 11. Apparatus according to claim 10,wherein the hybrid electrode comprises a core section including thesensing electrode, enclosed within an annular section including the atleast one stimulation electrode.
 12. Apparatus according, to claim 11,wherein the annular section comprises a carbon material.
 13. Apparatusfor modifying cardiac output of the heart of a subject, comprising: oneor more sensors, which sense signals responsive to cardiac activity; astimulation probe comprising one or more stimulation electrodes, whichapply non-excitatory stimulation pulses to a cardiac muscle segment; andsignal generation circuitry, coupled to the one or more sensors and thestimulation probe, which circuitry receives the signals from the one ormore sensors and generates the non-excitatory stimulation pulses,responsive to the signals, wherein the one or more sensors comprise ahemodynamic sensor, which generates signals responsive to blood flow.14. Apparatus for modifying cardiac output of the heart of a subject,comprising: one or more sensors, which sense signals responsive tocardiac activity; a stimulation probe comprising one or more stimulationelectrodes, which apply non-excitatory stimulation pulses to a cardiacmuscle segment; and signal generation circuitry, coupled to the one ormore sensors and the stimulation probe, which circuitry receives thesignals from the one or more sensors and generates the non-excitatorystimulation pulses, responsive to the signals, wherein the one or moresensors comprise a hemodynamic sensor, which generates signalsresponsive to blood oxygenation.
 15. Apparatus for modifying cardiacoutput of the heart of a subject, comprising: one or more sensors, whichsense signals responsive to cardiac activity; a stimulation probecomprising one or more stimulation electrodes, which applynon-excitatory stimulation pulses to a cardiac muscle segment; andsignal generation circuitry, coupled to the one or more sensors and thestimulation probe, which circuitry receives the signals from the one ormore sensors and generates the non-excitatory stimulation pulses,responsive to the signals, wherein the one or more sensors comprise ahemodynamic sensor, which generates signals responsive to a temperature.16. A method for modifying cardiac output, comprising: applying astimulation probe comprising one or more stimulation electrodes to asubject's heart; receiving a signal from at least one sensor responsiveto the subject's cardiac muscle activity; and generating anon-excitatory stimulation pulse responsive to the signal and conveyingthe pulse to at least one of the one or more electrodes, whereinapplying the stimulation probe comprises applying a probe comprising aplurality of stimulation electrodes, and wherein generating andconveying the pulse comprises generating a sequence of pulses andapplying each pulse in the sequence to a different one of the pluralityof stimulation electrodes.
 17. A method for modifying cardiac output,comprising: applying a stimulation probe comprising one or morestimulation electrodes to a subject's heart; receiving a signal from atleast one sensor responsive to the subject's cardiac muscle activity;and generating a non-excitatory stimulation pulse only at a time atwhich it is unable to propagate action potentials responsive to thesignal and conveying the pulse to at least one of the one or moreelectrodes, wherein generating and conveying the pulse comprisesdetecting a cardiac arrhythmia and adjusting the application of thepulses responsive thereto.
 18. A method for modifying cardiac output,comprising: applying a stimulation probe comprising one or morestimulation electrodes to a subject's heart; receiving a signal from atleast one sensor responsive to the subject's cardiac muscle activity;and generating a non-excitatory stimulation pulse responsive to thesignal and conveying the pulse to at least one of the one or moreelectrodes, wherein generating and conveying the pulse comprisesdetecting a QT interval in the signals and generating pulses responsivethereto.
 19. A method for modifying cardiac output, comprising: applyinga stimulation probe comprising one or more stimulation electrodes to asubject's heart; receiving a signal from at least one sensor responsiveto the subject's cardiac muscle activity; and generating anon-excitatory stimulation pulse responsive to the signal and conveyingthe pulse to at least one of the one or more electrodes, wherein thepulse comprises a baseline pulse and a waveform of substantially higherfrequency than the baseline pulse superimposed thereon.
 20. A methodaccording to claim 8, wherein the waveform comprises a square wave. 21.A method according to claim 8, wherein varying the extent comprisesselectively addressing a net of stimulation electrodes implanted in theheart.
 22. A method for modifying cardiac output, comprising: applying astimulation probe comprising one or more stimulation electrodes to asubject's heart; receiving a signal from at least one sensor responsiveto the subject's cardiac muscle activity; and generating anon-excitatory stimulation pulse responsive to the signal and conveyingthe pulse to at least one of the one or more electrodes, whereinapplying the stimulation probe comprises varying the extent of a portionof the area of the heart segment to which the stimulation pulse isapplied.
 23. A method for modifying cardiac output, comprising: applyinga stimulation probe comprising one or more stimulation electrodes to asubject's heart; receiving a signal from at least one sensor responsiveto the subject's cardiac muscle activity; and generating anon-excitatory stimulation pulse responsive to the signal and conveyingthe pulse to at least one of the one or more electrodes, whereinapplying the stimulation probe comprises inserting at least one of theone or more stimulation electrodes into the coronary sinus.
 24. A methodaccording to claim 23, wherein inserting the at least one stimulationelectrode comprises inserting the electrode into the coronary sinus. 25.A method according to claim 23, wherein sensing the hemodynamicparameter comprises sensing cardiac output, and wherein generating thepulse comprises changing the pulse responsive to the signal to increasethe cardiac output.
 26. A method according to claim 23, wherein sensingthe hemodynamic parameter comprises sensing cardiac output, and whereingenerating the pulse comprises changing the pulse responsive to thesignal to decrease the cardiac output.
 27. A method according to claim23, wherein sensing the hemodynamic parameter comprises sensing apressure.
 28. A method according to claim 23, wherein sensing thehemodynamic parameter comprises sensing a flow rate.
 29. A methodaccording to claim 23, wherein sensing the hemodynamic parametercomprises sensing oxygenation.
 30. A method according to claim 23,wherein sensing the hemodynamic parameter comprises sensing atemperature.
 31. A method for modifying cardiac output, comprising:applying a stimulation probe comprising one or more stimulationelectrodes to a subject's heart; receiving a signal from at least onesensor responsive to the subject's cardiac muscle activity; andgenerating a non-excitatory stimulation pulse responsive to the signaland conveying the pulse to at least one of the one or more electrodes,wherein receiving the signal comprises sensing cardiac output, andwherein generating the pulse comprises changing the pulse responsive tothe signal to increase the cardiac output.
 32. A method for modifyingcardiac output, comprising: applying a stimulation probe comprising oneor more stimulation electrodes to a subject's heart; receiving a signalfrom at least one sensor responsive to the subject's cardiac muscleactivity; and generating a non-excitatory stimulation pulse responsiveto the signal and conveying the pulse to at least one of the one or moreelectrodes, wherein receiving the signal comprises sensing cardiacoutput, and wherein generating the pulse comprises changing the pulseresponsive to the signal to decrease the cardiac output.
 33. A methodfor modifying cardiac output, comprising: applying a stimulation probecomprising one or more stimulation electrodes to a subject's heart;receiving a signal from at least one sensor responsive to the subject'scardiac muscle activity; and generating a non-excitatory stimulationpulse responsive to the signal and conveying the pulse to at least oneof the one or more electrodes, wherein receiving the signal comprisessensing a pressure.
 34. A method for modifying cardiac output,comprising: applying a stimulation probe comprising one or morestimulation electrodes to a subject's heart; receiving a signal from atleast one sensor responsive to the subject's cardiac muscle activity;and generating a non-excitatory stimulation pulse responsive to thesignal and conveying the pulse to at least one of the one or moreelectrodes, wherein receiving the signal comprises sensing a flow rate.35. A method for modifying cardiac output, comprising: applying astimulation probe comprising one or more stimulation electrodes to asubject's heart; receiving a signal from at least one sensor responsiveto the subject's cardiac muscle activity; and generating anon-excitatory stimulation pulse responsive to the signal and conveyingthe pulse to at least one of the one or more electrodes, whereinreceiving the signal comprises sensing oxygenation.
 36. A method formodifying cardiac output, comprising: applying a stimulation probecomprising one or more stimulation electrodes to a subject's heart;receiving a signal from at least one sensor responsive to the subject'scardiac muscle activity; and generating a non-excitatory stimulationpulse responsive to the signal and conveying the pulse to at least oneof the one or more electrodes, wherein receiving the signal comprisessensing a temperature.
 37. A method for modifying cardiac output,comprising: applying a stimulation probe comprising one or morestimulation electrodes to a subject's heart; receiving a signal from atleast one sensor responsive to the subject's cardiac muscle activity;and generating a non-excitatory stimulation pulse responsive to thesignal and conveying the pulse to at least one of the one or moreelectrodes, wherein generating and conveying the pulse comprisesgenerating and conveying pulses at selected times of day.
 38. A methodaccording to claim 37, wherein generating and conveying the pulsecomprises generating and conveying pulses at selected times of day. 39.A method according to claim 38, wherein generating and conveying thepulses at selected times of day comprises conveying pulses to increasecardiac output during the subject's waking hours.
 40. A method formodifying cardiac output, comprising: applying a stimulation probecomprising one or more stimulation electrodes to a subject's heart;receiving a signal from at least one sensor responsive to the subject'scardiac muscle activity; and generating a non-excitatory stimulationpulse responsive to the signal and conveying the pulse to at least oneof the one or more electrodes, wherein conveying the pulses comprisesapplying pulses to a heart segment having an area of at least 1 cm². 41.A method according to claim 40, wherein applying the pulses comprisesapplying pulses to a heart segment having an area of at least 1 cm². 42.A method according to claim 41, wherein applying the pulses comprisesapplying pulses to a heart segment having an area of at least 4 cm².